Abstract

LB-23

The Notch pathway, which regulates cell growth and differentiation, is activated in a variety of human cancers including T-cell Acute Lymphoblastic Leukemia (T-ALL). Gamma-Secretase Inhibitors (GSI) capable of blocking Notch receptor cleavage and activation are being evaluated as cancer therapy for those tumors harboring an activated Notch pathway. Here we utilize the GSI MRK-003 and xenograft models of T-ALL to provide support for the development of GSIs in the treatment of cancer. Continuous treatment of mice with MRK-003 was not tolerated due to body weight loss, thought in part to result from mechanism-based conversion of intestinal epithelium to a secretory lineage that can be measured by Periodic Acid Schiff (PAS) staining. PAS staining was used as a functional marker to measure recovery time of mouse intestine following GSI treatment and guide selection of dose regimens. Either thrice-weekly or once weekly administration of MRK-003 was well tolerated and provided prolonged Notch pathway inhibition as measured by the formation of Notch intracellular domain (NICD) and Notch target genes in xenograft tumors. Target inhibition correlated with the efficacy in xenograft models of T-ALL. We provide evidence that these anti-tumor effects are the result of apoptosis induced by a mechanism involving disruption of mitochondrial membrane potential.